The human genome consisted of DNA polymers having an enormous amount of information which is not capable of being substituted with general synthetic compounds. In the last decade, progress in recombinant DNA technologies has enabled remarkable discovery and/or production of a large number of physiologically active proteins and many of them with therapeutic potential have been used as biopharmaceuticals. Where certain diseases and the damage of organs are not treatable with natural recovery, the use of artificial material based on a high molecular weight polymer can be very useful. Moreover, most of these medical polymer materials may provide with better biocompatibility, suitability, and pharmacokinetics than conventional material. The use of polymer compositions, particularly, consisting of synthetic polymer in the field of medical and biotechnology. In contrast to most of naturally derived compositions, synthetic polymer compositions can be formulated to exhibit predetermined physical characteristics such as gel time, gel strength, as well as biological characteristics such as degradability. Among these polymer, polyethylene glycol (PEG) and its derivatives has been used most frequently for implants or sealants by means of its non-immungenic and hydrophilic characteristics.
Polyethylene glycol (PEG) is amphiphilic that is soluble not only in water but also in organic solvents. Therefore, even poorly soluble material in water can be converted to possess hydrophilicity when conjugated with PEG. PEG is known to be weakly immunogenic and almost nontoxic to human, thus can be useful in a number of clinical applications. When a PEG conjugate is administered to biological systems, characteristics of extended residence time and reduced rate of renal clearance are often observed. For examples, U.S. patents (U.S. Pat. No. 5,977,163 and U.S. Pat. No. 5,648,506) described PEG-taxol conjugates wherein the taxol is used for a pharmaceutical treatment for ovarian and mammaian cancers. While taxol is known to be extremely water insoluble to make it difficult to be formulated as a parenteral, the PEG-taxol, a PEG-conjugated form of taxol, demonstrated improved water solubility more than 1000 times than that of natural taxol.
In general, PEG is a linear polymer with the hydroxyl group at the terminals. The chemical structure of PEGs is HO—CH2CH2O—(CH2CH2O)n—CH2CH2OH (PEG) or CH3O—CH2CH2O—(CH2CH2O)n—CH2CH2OH (methoxy PEG). The linear PEGs having just one or two end groups, have limited reactivity. However, if a larger number of end groups per PEG molecule, their reactivity will be remarkably improved. To obtaining PEGs having more terminals, their structure has to take up the form of the PEG wherein multiple PEG arms are produced from one single core. For example, U.S. Pat. No 6,312,725 B1 discloses a 4-arm PEG prepared by common and commercially available ethylene oxide addition reaction using pentaerythritol as the core of star PEG. Preparation of 12-arm PEG, the 4-arm sulfhydryl PEGs have to be conjugated with the 4 ends of the pentaerythritol prior to make a core with 12 ends. However, there has not been suggested or disclosed of 6-arm PEG in above reference cited herein.
PEG has been applied for a variety of applications in the biotechnology field. Block copolymers of Pluronic® and Poloxamer® insoluble in cold water in nature are formed into insoluble hydrogels at body temperature when administered into human body (Leach, et al., Am. J. Obstet. Gynecol., 162, pp1317-1319, 1990). Polymerizable cyanoacrylates have been also described for use as tissue adhesives (Ellis, et al., J. Otolaryngol., 19, pp68-72, 1990). In yet another approach, two-part synthetic polymer compositions have been described that they, when mixed together, form covalent bonds with one another, as well as with exposed tissue surfaces (PCT WO 97/22371, which corresponds to U.S. application Ser. No. 08/769,806 U.S. Pat. No. 5,874,500). In a similar approach involving a two-part composition, the mixture of protein and bifuntional crosslinking agent has been described for use as a tissue adhesive (U.S. Pat. No. 5,583,114).
U.S. Pat. No. 5,162,430, issued Nov. 10, 1992 to Rhee et al., and commonly owned by the assignee of the present invention, discloses collagen-synthetic polymer conjugates prepared by covalently binding collagen to synthetic hydrophilic polymers such as various derivatives of polyethylene glycol.
Commonly owned U.S. Pat. No. 5,324,775, issued Jun. 28, 1994, to Rhee et al., discloses various insert, naturally occurring, biocompatible polymers (such as polysaccharides) covalently bound to synthetic, non-immunogenic and hydrophilic polyethylene glycol polymers.
Commonly owned U.S. Pat. No. 5,328,955, issued July 12, to Rhee et al., discloses various activated forms of polyethylene glycol and various linkages which can be used to produce collagen-synthetic polymer conjugates having similar range of physical and chemical properties each other.
Commonly owned, copending U.S. application Ser. No. 08/403,358, filed Mar. 14, 1995, discloses a crosslinked biomaterial composition prepared by using a hydrophobic crosslinking agent, or a mixture of hydrophilic and hydrophobic crosslinking agents. Preferred hydrophobic crosslinking agents include any hydrophobic polymer that contains or can be chemically modified to contain two or more succinimidyl groups.
Commonly owned, copending U.S. application Ser. No. 8/403,360, filed Mar. 14, 1995, discloses a composition useful in the prevention of surgical adhesions comprising a substrate material and an anti-adhesion binding agent; where the substrate material preferably comprises collagen and the binding agent preferably comprises at least one tissue-reactive functional group and at least one substrate-reactive functional group.
Commonly owned, U.S. application Ser. No. 08/476,825, filed Jun. 7, 1995, by Rhee et al., discloses bioadhesive compositions comprising collagen crosslinked with a multifunctionally activated synthetic hydrophilic polymer, as well as methods of using such compositions to effect the adhesion between the first surface and the second surface, wherein at least one of the first and second surfaces is preferably a native tissue surface.
Japanese patent publication No. 07090241 discloses a composition used for temporary adhesion of a lens material to a support, to mount the material on a machining device, comprising a mixture of PEG having an average molecular weight in the range of 1000-5000 D and poly-N-vinylpyrrolidone having an average molecular weight in the range of 30,000-200,000 D.
West and Hubbell disclose the prevention of post-operative adhesions using a photopolymerized PEG-co-lactic acid diacrylate hydrogel and a physically crosslinked PEG-co-polypropylene glycol hydrogel, Poloxamer 407.RTM® (West and Hubbell, Biomaterials, 16, pp1153-1156, 1995).
U.S. Pat. No. 5,874,500 disclosed polymeric compositions comprising a group of synthetic polymers containing multiple nucleophilic groups and another group of synthetic polymers containing multiple electrophilic groups and the methods for using these compositions to affect adhesion between the first surface and the second surface wherein at least one of the surfaces is preferably a native tissue surface, which can be used to bring about the augmentation of tissue, or to prevent surgical adhesion, or to coat surfaces of synthetic implants, or to deliver drugs or other active agents, or for ophthalmic applications. The use of polymeric compositions with biological materials such as hydrogel of polymer-collagen, may be useful as bioadhesives in place of surgical sutures or for use in ophthalmic application. In transplantation of skin or cells under clinical situation, the composition can be used as the matrix housing the transplant cells or connecting the skin. These polymeric compositions can also be used as a large space-filling device for organ displacement in a body cavity during surgical or radiation procedures, for example, to protect the intestines from a planned course of radiation to the pelvis.
Each publication cited above and herein is incorporated herein by reference in its entirety to describe and disclose the subject matter for which it is cited.
The present inventors have endeavored to synthesize a novel 6-arm PEG and its derivatives, and finally completed that the biodegradable composition comprising synthetic polymers which contain multiple nucleophilic groups using synthetic polymers containing multiple electrophilic groups, and the methods for using these compositions to effect the augmentation of tissue, or to prevent surgical adhesion, or to coat surfaces of synthetic implants.